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The Journal of Neuroscience, April 23, 2008, 28(17):4501-4511; doi:10.1523/JNEUROSCI.2844-07.2008

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Neurobiology of Disease
A Destructive Interaction Mechanism Accounts for Dominant-Negative Effects of Misfolded Mutants of Voltage-Gated Calcium Channels

Alexandre Mezghrani,^1 * Arnaud Monteil,^1 * Katrin Watschinger,² Martina J. Sinnegger-Brauns,² Christian Barrère,¹ Emmanuel Bourinet,¹ Joël Nargeot,¹ Jörg Striessnig,² and Philippe Lory¹

¹Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5203, Institut de Génomique Fonctionnelle, Institut National de la Santé et de la Recherche Médicale, Unité 661, and Université Montpellier, 34094 Montpellier, France, and ²Abteilung Pharmakologie und Toxikologie, Institut für Pharmazie und Centrum für Molekulare Biowissenschaften Innsbruck, Universität Innsbruck, A-6020 Innsbruck, Austria

Correspondence should be addressed to either Alexandre Mezghrani or Philippe Lory at the above address. Email: alexandre.mezghrani{at}igf.cnrs.fr or Email: philippe.lory{at}igf.cnrs.fr

Channelopathies are often linked to defective protein folding and trafficking. Among them, the calcium channelopathy episodic ataxia type-2 (EA2) is an autosomal dominant disorder related to mutations in the pore-forming Ca_v2.1 subunit of P/Q-type calcium channels. Although EA2 is linked to loss of Ca_v2.1 channel activity, the molecular mechanism underlying dominant inheritance remains unclear. Here, we show that EA2 mutants as well as a truncated form (D_I-II) of the Ca_v3.2 subunit of T-type calcium channel are misfolded, retained in the endoplasmic reticulum, and subject to proteasomal degradation. Pulse-chase experiments revealed that misfolded mutants bind to nascent wild-type Ca_v subunits and induce their subsequent degradation, thereby abolishing channel activity. We conclude that this destructive interaction mechanism promoted by Ca_v mutants is likely to occur in EA2 and in other inherited dominant channelopathies.

Key words: voltage-gated calcium channel; P/Q-type; T-type; dominant-negative activity; episodic ataxia type 2; misfolding; endoplasmic reticulum; proteasome

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Received June 22, 2007; revised Feb. 6, 2008; accepted Feb. 29, 2008.

Correspondence should be addressed to either Alexandre Mezghrani or Philippe Lory at the above address. Email: alexandre.mezghrani{at}igf.cnrs.fr or Email: philippe.lory{at}igf.cnrs.fr

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